Indian Journal of Experimental Biology Vol. 37, October 1999, pp. 952-958

Interaction between N-methyl-D-aspartate recepto'r antagonists and imipramine in shock-induced depression

H K Chaturvedi*, Dinesh Chandra & J S Bapna**

Department of Pharmacology, Maula!1a Azad Medical College, New Delhi 110 002. India

Received 24 Febrtw/), 1999; revised 15 July 1999

In the past few years, literature has accumulated describing manifestation of seizures following administration of certain antidepressants. Such reports are of particular importance because depression is a freq uent psychiatric prob lcm associatcd with epilepsy. Therefore, in the view of the fact t.hat NMDA receptor ant agonists have been rcportcd to reduce behavioural deficits and have been shown to be ant iconvu lsant. it was considered imperative to study thcir antidcpressant d lcct lI si ng shock-induced depression model in mice. Presentation of inescapable foot shock significant ly reduced <l mbulati on and rearing in the open field arena and increased immobility duration in the FST. Pretreatment with imipramine. M K 80 I ;1I1U

ketamine significantly prevented the effect of shock. Also. the combination of imipramine with ei ther of the NMDA antagonists antagon ised the effect of shock. Haloperidol , prazosin and ketanserin pretreatment modi lied the effect of these agents. These find ings suggest an antidepressant elTect of the NMDA receptor antagoni sts. and a complexi lY of neurotransmitter mechanisms. which are responsible for the occurrence of behaviou ral effects in shock-induced dep ression model.

The possibility that drugs that block N-methyl­D-aspartate (NMDA) receptors have some therapeutic benefit is being investigated in detail. It has been shown that over-activation of NMDA receptors may be involved in several human neuropathologies l

.2

.

The high affinity of the NMDA receptor antagonists for their receptors, rapid CNS penetration, long duration of action and uncompetetive antagonism makes these compounds attracti ve and potential candidates for clinical trial s. Of these MK 80 I has been widely studied and is a potent anticonvulsant in a range of animal se izure models:1.4. Indeed MK 80 I has been tested as anticonvulsant in human cli nical trials as an add-on drug for patients with refractory complex partial seizures5

.

Literature is avai lable describing manifestation of seizures following administration of certain antidepressants6

,7. Aggarwal et al. R compared a few antidepressants with the epi leptogenic response in laboratory situations. Such reports are of particular importance because depression IS a frequent psychiatric problem associated with ep ileps/.

Present address: *1. K. Drugs & Pharmaceuti cals Ltd .. Milap Niketan . 8 Bahadur Shah Zafar Marg, New Delhi 110002, India Fax: 91-1 1-3350993; Emai l h-chaturvedi @hotmai l.com **Institute of Human Behaviour & Allied Sciences, Dilshad Garden, Delhi 110095, India

Therefore, in view of the fac t that J\MDA receptor antagonists have been reported to reduce behavioural deficits lO and have been shown to be devo id of

I . . 11 -11. 'd d' . convu sant act Ivity . It was consl ere Imperati ve to study the ant idepressant effect of NM DA receptor antagonists .

Materials and Methods Animals-Adult alb ino mI ce of e ither sex ,

weighing 25±5g, rai sed in the Central Animal Facility of Maulana Azad Med ical College. were used in the study. They were maintained at a 12 hr day/ni ght cycle, and were acclimatized to the laboratory conditions 24 hr before testing and had free access ro food and water. The animal s were drawn at random for test and contro l groups _ The study was conducted between 0800 and 1200 hrs .

Drugs-The dru gs used in the present study were imipramine hydrochloride (Torrent harmaceulicals Ltd .), MK 80 I (Merck Research Laborarories) , ketamine hydrochl oride (Themis Chemica ls Ltd. ), prazosin hydrochloride (S igma Chemical Co.), haloperidol (Searle India Ltd.), and kctanserin tartarate (Janssen Pharmaceutica). All th e drugs were freshly prepared In saline and were injected intraperitoneally in a volume of 5mllkg_

While imipramine, MK 80 J and ketamine were administered 30 min before; prazosi n, haloperidoi and

CHATURVEDI e/ al.: NMDA RECEPTOR ANTAGONISTS & ANTIDEPRESSANT EFFECT 953

ketanserin were administered 60 min before crivincr b b

the shock. Control animals received 0.9% saline.

Shock-induced depressioll-The method was adop­ted as earlier I4-16

•

(i) Delivery of Shock : Four mice were placed on a grid floor (26x26 cm) made of stainless steel rods (2 mm diameter, pl aced I cm apart) connected in series. The animals were prevented from escaping or coming in contact with each other by in verting separate glass beakers over all four of them. The grid fl oor was connected to a programmable electric shock generator (Medicare Research Stimulator SB 44, Recorders and Medicare Systems, India). The stimulator was programmed to deliver 360 foot shocks (300 ~A) of 2 sec duration at intervals of 9 sec. The animals were shocked for a total of I hr. Spec ial attenti on was paid to keep the grid clean from faeca l matter to avoid short circuits terminatin g the shock delivery. Control animal s Were merely pl aced on the grid under in verted beakers for I hI' but were not shocked.

(ii ) Behavioura l Testing: Twent y-four hours after the shock admin istration , behavioural depress ion was measured by an open fi e ld test (OFT) fo ll owed by a forced swimming tes t (FST). The OFT was carried out in a circular wooden arena (84 cm di ameter, 30 cm hi gh) with a white sun mica base, with three concentri c circles di vided in to segments by rad ial lines ori ginating from the centre. Each animal was tested for 5 min . Ambulat ion (locomotor behav iour) was measured as number of lines crossed by an an imal , and reari ng (ex ploratory activity) was measured as number of times the an imal stood on its hind limbs with or wi thout the support of circul ar wall. The count ing of ambu iati on and rearing responses was done using a hand operated counter. Immediately after the behaviour testing procedu re the anima ls were subj ected to FST. The ani mal s were forced to swi m individuall y, fo r 6 min, in a glass beaker ( I I cm diameter, 15 cm hi gh) containing fresh water upt o a height of 6 cm and maintained at a temperature of 22°± 1°C. Each animal made vigorous attempts to get out of glass beaker during the first few minutes and thereafter surrendered to the experimental conditions and became immobi le with occasional escape attempts. The total durat ion of immobility duri ng

the last 4 min of the 6 min tes t period was recorded.

Statistical analysis- The results are ex pressed as mean ± standard error of mean. Statistical an alys is of data was performed using Student 's t-test , one way analysis of variance (ANOY A) foll owed by either Dunnet's test or Tukey's multi ple range test, wherever appropriate.

Results Inescapable foot shock for hr significan tly

reduced ambulat ion and rearing when compared to no shock control in the OFT and increased immobility duration (P<O.OO I) in the FST (Table I).

Pretreatment with imipramine (8-32 mg/kg) . MK 80 1 (0.05-2 mg/kg) and ketamine C2 . .'i- IO mg/kg) significantl y reversed the c ffect of shock on behaviour. The onl y difference betwee n imiprami ne and other agents was that i mi prami ne fai led to antagonise the effect of foot ,hock on rearing behaviour. These observat ions are shown in Table 2.

Tab le 3 gives the modificati on of the effect of imipramine, MK 80 I and ketamine by haloperidol (0.1 mg/kg). Haloperidol per .1'(' did not modify the effect of inescapabl e foot shock. Though. the effect of Imipramine remained un altered in presence of haloperidol, the effect of both MK 801 and ketal1lin ' was antagoni sed. The effect of imipramine wi th el lilC' of the NMDA antagonist on ambuiati on and immobili ty duration were attenu ated by haloperidol. whereas the effect of th e combinat ions on reari ng \ a:-­a lso an tagoni sed by hal operi dol pretreatment.

The modifi cati on of the effect of imipramine. MK 80 I and ketami ne by prazosin (3 mg/kg) i · given in Table 4. Prazos in per se di d not mod ify the e ffect of inescapab le foot shock. The effec t of imipramine on ambulati on was an.tagoni sed by prazosin pretreat-

Tab le I-En'cci ofi nescapablc 1001 , hock Oil hchavillur I II mice

Co nl ro l

Shocked

Ambul ali on

I 59.50±5.42

SO.50±4.6 1 **

OFT FST Rearing Imlllohi lit y

22. IO±2.1' X2.20± .. 5 1

11.30± 1 .. Y " 15X.,)()±4J11 "*

OF r=open licld tes!. FST=fo rced swimming lesl. Results arc given as mean ± SE (n=I O) . Wh il e Ihe OFl ' values reprcsent number of episodes in 5 min , the FST values dellot c the durali oll of imillobil ity in iast 4 min or a 6 min test. **Pd ).OOI vs Will ro I using SllIdcnt's i-test. Both the groups were Ireated wi lh saline. Contro l ani mals werc pl aced Oil gnd but were not exposcd to

shock .

954 INDIAN J EXP SIOL, OcrOBER 1999

ment, whereas the effects of MK 80 J and ketamine remained unaltered . The effect of the combinations of imipramine with either of the NMDA antagonists on ambulation was attenuated by prazosi n pretreatment.

(4 mglkg). Though, ~etanserin per se failed to modify the effect of inescapable foot shock , it antagonised the effect of imipramine on immobili ty duration. Ketanserin failed to modify the effect of e ither of the NMDA an tagonists. The effect of co mbinati on of imipramine with both, MK 80 I and ketamine, on

Table 5 gives the modification of the effect of imipramine and NMDA antagonists by ketanserin

Tab le 2-Effect of imipramine, MK 80 I and ketami ne on shock-i nduced changes in behaviou r in mice

Treatment (mg/kg) Off FST Ambulation Rearing Immobi lit y (,ee)

Control 83.62 ± 4.60 10.25 ± 1.75 152.12 ± 7 .D

Imi pramine (8) 87.50 ± 4.50 10.25±1.14 150.25 ± 4 .7X

Imipramine ( 16) 106.75 ± 5.1 3** 12.25 ± 1.58 129.75 ± 4 .70'"

Imipramine (32) 129.12±5.01** 15. 12 ± 1.66 107. 25 ± 5.46**

Co ntrol 78.62 ± 4.98 10.25 ± 2.33 155.00 ± ."45

MK 80 1 (0.05) 94.12 ± 6.46 13.00 ± 1.08 141U)O ± 4 . T'o

MK 801 (0. 1) 112.62 ± 4.67** 18.25 ± 1.54** 122.25 ± 5. )l)*':'

MK 80 1 (0.2) 144.87 ± 6.04** 27.12±1.93** 77 .00 ± 4.79"':

Control 81.70±5.6 1 10. 10 ±1.75 155.20 ± 5.37

Ketamine (2.5) 86.37±5.15 14.37 ± 1.52 150.H7 ± 5.22

Ketamine (5) 100.25 ± 4.88** 20.75 ± 2.0 1 ** 132.62 ± 4 58 *

Ke tamine ( 10) 124.00 ± 6.74** 29.25 ± 2.44** 102.62 ± 4. 16**

OFf=open fi eld test, FST=forced swimming test. Resul ts are given as mean ± SE (n=IO). While the Off val ues represenr number of epi sodes in 5 min , the FST values denote duration of immob ility in last 4 min of a 6 min test. *P<0.05 and *·~ P<O .O I vs COI1lrol using ANOY A and Dunnett's test. Control (shocked) animals were ll\,ated with saline.

Table 3-Moditication of the effect of imipramine, M K 80 I and ketamine by haloperidol on shock- induced changes In behaviour in mice

Treat ment (mg/kg) Off FST Ambulation Rearing Immobility (sec)

Control 87.87 ± 5.24 12.00 ± 1.32 15H.75 ± 6.54

Haloperidol (0.1) 82.50 ± 6.25 10.00 ± 1. 87 160.75 ± 7.44

Imipramine (16) 11 2.37 ± 5.84** 12.25 ± 1.5X 132.62 ±3XF

Haloperidol (0. 1 )+Imipramine (16) 113.37 ± 5.79**" 11.75 ± 1.99 126.75 ± 4.6 1 **"

MK 80 1 (0.1) 11 8.38 ± 3.75** 18 .25 ± 1.54* 122.25 ± 5.59*':'

Haloperidol (0.1 )+M K 80 I (0. I ) 94.37±5.91" 11.75 ± 1.98" 150.00 ± 7.12'

Ketamine (5) 108.75 ± 6.07* 20.80 ± 1.39** 123.75 ± 5.27 **

Haloperidol (0. 1 )+Ketamine (5) 9 1.75 ± 5.39" I 1.1 4 ± 1. I 0" 151 .42±7.65"

Imipramine ( 16)+MK 80 1 (0. 1) 136.50 ± 3.26**1x: 27. 12± 1.08**1><: 89.75 ± 5 .77 **1 ....

Imipramine ( 16)+Ketamine (5) 136.33 ± 4.4 7 * * Ix: 29 .16 ±· 1.52**'" 95 .88 ± 5.2X **hc

Haloperidol (0.1 )+Imipramine ( 16)+M K 801 (0. 1) 115.75 ± 3.92**"" 14.00 ± 2.18.1 126.50 ± 5.49**,,,1

Halo peridol (0.1 )+Imipramine ( 16)+Ketamine (5) 111 .25 ± 5.88**,,1 13.25 ± 1.98 r 121un :± 4.80**"1

OFf=open field test, FST=forced swimming test. Results are given as mean ± SE (n=8- 1 0). While the Off val ues re present number of episodes in 5 min , the FST values denote duration of immohi lity in last 4 mi n of a 6 min test. *P<O.05 and **P<O.O I vs co ntrol usi ng ANOY A and Dunnett 's test. Other comparisons : " vs Haloperidol (0.1); h vs Imipramine ( 16); " vs M K IiO I (0.1 ); .I vs Imipramine (16)+MK 80 I (0 .1 ); c Ys Ketamine (5) and r vs Imipramine (l6)+Ketamine (5) using ANOY A and Tukey's mu lti ple range tes t at 5% level. Control (shocked) animals were treated with saline.

CHATURYEDI et al.: NMDA RECEPTOR ANTAGONISTS & ANTIDEPRESSANT EFFECT 955

immobility duration was attenuated by ketanserin pretreatment.

Discussion Exposure to uncontrollable stress is well known to

cause physiological and behavioural alterations in a

wide variety of experimental situations I 7-1'} Similarly,

in the present study, inescapable foot shock produced a depression of both ambulati on and rearing behaviour of mice in the OFf and increased the duration of immobility in the FST. Th ough. our findings are in agreement with those of earlier

Table 4-Moditication of the effect of imipramine, MK 80 I and ketamine by prazosin on the shock-induced changes in behaviour in mice

Treatment OFT FST (mg/kg) Ambulati on Rearing Im mobili lY (sec)

Cont rol 88.00 ±7.64 11.50 ± 1.88 153.fi2 ± 6.1 3

Prazosin (3) 89.87 ± 5.05 12.50 ± 1.62 154.62 ± 7.<)()

Imipramine (16) 11 5.50 ± 5.67* 10.3 1 ± 1.48 126.88 ± 4.8 1*

Prazosin (3)+Imipramine ( 16) 94.87 ± 6.331> 12.50 ± 2.27 12<).fi2 ± 5.49 ""

MK801(0.1) 112.62 ± 4.67* 17.69 ± 1. 20* 124.50 ± 4.44"'*

Prazosin (3)+MK 80 1 (0.1) 115.25 ± 5.76*" 18. 12±1 .63 *" I I X.OO ± 5.61"' *·1

Ketamine (5) 11 3.00 ± 4.73** 20.65 ± 1.46** 133.38 ± 5.<):F

Prazosin (3)+Ketamine (5) 115.38 ± 5.14**" 18.00 ± 1.63 *" I n .87 ± 6. 1 1**"

Imipramine (l6)+MK 80 I (0.1) 141.87 ± 4.39* *oc 26. 10 ± 1.32**1>" 83.50 ± 6.03*"lx·

Imipramine (I6)+Ketamine (5) 136.75 ± 5.45**hc 28 .21 ± 1.20**1>.: 8<) .88 ± 7.4 1 Mix'

Prazosin (3)+Imipramine (16)+M K 80 1 (0. 1) 128.25 ± 6.34**" 26.62 ± 2.0 1**" 93.25 ± 7.". I **"

Prazosin (3)+Imipramine (16)+Ketamine (5) 114.12 ± 4.47**,,1" 27.75 ± 1.58*"" 100.25 ± 6. 17"00""

OFT=open field test. FST=forced swimming test. Results are given as mean ± SE (n=S- 1 0). While the OFT val ues represenl numbcr of episodes in 5 min , the FST values denote duration of immobility in last 4 min of a 6 min test. *1'<0.05 and **Pdl.O I vs control usi ng ANOYA and Dunnett's test. Other comparisons: a vs Prazosin (3); I> vs Imipramine (16);" vs MK XO I (0. 1): d vs Imipraminc (16)+MK 801 (0.1) ; C vs Ketamine (5) and I" vs Imipramine (I6)+Ketamine (5) using ANOY A and Tukey's multipl e range rest at 5% level. Control (shocked) animals were treated with saline.

Table 5-Modification of the effect of imipramine, MK SO I and ketamine by ketanserin on shock-i nduced changes in hehaviour in mi ce

Treatment OFT FST (mg/kg) Ambulation Rearing Iml1lohilit y (sec)

Control ')0.12 ± 6.38 10.50 ± 2. 17 156.:\7 ± 6.60

Ketanserin (4) 89.22 ± 5.03 10.44± 1.4 1 152.77 ± 7.".4

Imipramine (16) 11 8.25 ± 5.53 ** 11.28 ± 1.26 124.87 ± 4.89"*

Ketanserin (4)+Imipramine (16) 11 8.50 ± 5.65 **" 12.20 ± 2.0X 157.90 ± 6.07"

MK 801 (0.1) 119.75 ± 4.S5** 20.81 ± 1.32* I 14.87 ± 4.85 **

Ketanserin (4)+MK 801 (0.1 ) 117.88 ± 5.69**" 19.88 ± 2.01 *" 12 1.77 ± 4.08 **"

Ketamine (5) 109.75 ±4.99** 19.X 1 ± 1.67 * 126.50 :t 5.80"" Ketanserin (4)+Ketamine (5) 11 2.00 ± 6.44**" IS .87 ± 2.93*" 1 19.62 ± 5.55 **"

Imipramine ( 16)+MK 80 I (0.1) 140.25 ± 5.49**oc 2S.26 ± 1.40**1>0 79 .". 8 ± .+ .4O**'K

Imi pramine ( 16)+Ketamine (5 ) 138.85 ± 5.37**hc 27.50 ± / .39**1,.- 84.25 ± 6.07 *,,1, '

Ket anserin (4)+Imipramine (16)+M K 80 1 (0.1) 142.30 ± 4.67 **" 29.00 ± 3.08 **" 127 .X8±5.78**"d

Ketanserin (4)+Imipramine (16)+Ketamine (5) 134.37 ± 4.8 1 **" 28.87 ± 1.4 1 *" " I 1 X.25 ± :'l.43'i'*'"

OFT=open field test, FST=forced swimmi ng test. Results are given as mean ± SE (n=8- 1 0). Whil e the OFT values represent number of episodes in 5 min. the FST values denOle duration of immobility in last 4 min of a 6 min test. *P<0.05 and **P<O.OI vs control using ANOY A and Dunnett's test. Other compari sons: a vs Ketanserin (4): I> vs Imipramine (16): C vs MK 80 I (0. i 1: d vs Imipramine ( 16)+M K 801 (0.1): C vs Ketamine (5) and I vs Imipramine (16)+Ketamine (5) using ANOY A and Tuke)L's multiple range lest at 5% level. Control (shocked) animals were treated with saline.

INDIAN J EX'p BIOL. OCTOBER 1999

workersI5.20.21, they differed from those of Plaznik et

al. 15, who reported a weaker effect of inescapable foot shock on the FST than in the OFT. It has been demonstrated that the behavioural disturbances induced by inescapable shock not only varied across individual mice with in a strain , but also varied across the strain I6.22.

In the present work, both NMDA receptor antagonists , MK 80 I and ketamine antagonised the effect of inescapable foot shock in a dose dependent fashi on. The increased ambulation and rearing in the OFT and decreased duration of immobility in the FST due to these agents was antagonized by haloperidol pretreatment. Prazosin and ketanserin fai led to modify these effects. These results are in agreement with Meloni et al 2J who have shown that dizocilpine (MK 80 I) diminishes the beha vioural deficit produced by learned helplessness. An indirect dopamine (DA) activation , through blockade · of NMDA receptors, has been proposed for MK 80 I by a number of workers24.26. Recently it has been demonstrated that haloperidol acts as a se lective inhibitor of MK 80 I binding to the NMDA receptors27 . Furthermore, two well-known major inputs to the striatum are the dopaminergic nigrostriatal bundle and the glu tamatergic corticostriatal projections28

.3o. There is considerable

evidence indicating an interaction between these two h 1 1 1? V · 11 pat ways' .. -. erma and KulkarnI ' reported that

various depaminergic blockers including haloperidol antagonized the MK 80 I induced stereotypic behaviour in nai've mice. Furthermore, Irifune et al. 34

have shown that ketamine induced locomotion is an tagonized by haloperidol , in a dose which does not affect spontaneous locomotor activity . Moreover, the destruction of dopaminergic neurons resulted in the suppression of ketamine-induced locomotor activity, suggesting that the presence of intact dopaminergic neurons was indispensable for the response of ketamine. They also demonstrated that a-nora·dr­energic antagonists did not inhibit ketamine-induced hyperlocomotion. Our finding that prozosin was not able to antagonize the effect of ketamine also support the view of the earlier workers . Similarly, the effect of MK 80 I was not antagonized by prazosin pre­treatment.

Acute uncontrollable stressors have been shown to increase the utilization of catecholamines and serotonin (5-HT), leading to reduced levels of these

. . . . f h b . 1516 monoammes m vanous regIons 0 t e ram'· ...

Behavioural depression followin g an acure stressor might result from tryptaminergic mechanisms37 or may be attributed to a motor acti vation deficit stemming from reduction of norepinephrine (NE)3H. As imipramine i.s a presynapti c uptake inhibitor of 5-HT and NE19

.40, it is logica l that thi s dru g could correct the behavioural depress ion cl ue to acute inescapable foot shock by increasing the intrasynaptic availability of NE and 5-HT. In the present work , effect of imipramine on open fi eld behaviour was antagonised by aI-adrenergic antagonist prazos in and not by haloperidol or ketanse ri n. whereas its immobility reducing effect was antagoni zed by ketanserin pretreatinent and not by any other antagoni st used. Our findin gs are in line with the work of Plaznik et at. 15. who demonstrated that administration of N-chl oroeth yl-2. 2-d ibrolllobenzy l­amine hydrochloride (DSP-4) , a se lecti ve neurotox in for noradrenergic neurons, decreased onl y open field behaviour and had no effec t on t e duration of immobility in the FST. Furthermore, it has been shown that maprotiline, a selecti ve NE reuptake inhibi tor, prevented the depress ion of the open fi eld behaviour leaving the durati on of immobility in the FST unaltered21.

In our work, imipramine fai led to restore the effect of inescapable foot shock on rearing behaviour, It has been shown that DA plays an important role in rearing activit/ I. As imipramine is a weak uptake inhibitor of DA42, therefore, it fail ed to restore the effect of shock on rearin g behaviour. Similar observation has been made by Pal and Dandi y} l.

The present findings demonstrate the effect of imipramine in the. OFT is medi at ~d through the noradrenergic and in the FST through tryptaminergic pathway as the immobility redu ing effect of imipramine in the FST was antagonized by ketanserin pretreatment only.

Furthermore, in the present study. th e concomitant administration of either MK 80 I or ketamine with imipramine produced a greater reduction in shock­induced behavioural depression than either of the drugs alone. The effect of concomitant administration of imipramine with either of the NMDA receptor antagonists on ambulatory activity of mi ce in the OFT was attenuated by both haloperidol and prazosin pretreatment. As both endogenous E and DA are considered to affect the locomotor acti vity these findings are not unexpected~1 . Though. imipramine treatment did not prevent the suppressant effect of

CHATURVEDI et al.: NMDA RECEPTOR ANTAGONISTS & ANTIDEPRESSANT EFFECT 957

inescapable foot shock on rearing activity of mice, its combination with MK 80 I or ketamine increased the rearing. This effect of the combination of imipramine with NMDA receptor antagonists was antagonized -by haloperidol pretreatment. The DA reuptake inhibition by imipramine does not explain this effect fully, as imipramine is a weak DA uptake inhibitor42

. As both the typical and atypical antidepressants have been shown to increase DA releasing effect of NMDA receptor antagonists44

, our finding is not surprising, and suggests a common effector pathway through DA. Furthermore, the immobility reducing effect in the FST due to concomitant administration of imipramine and either of the NMDA receptor antagonists was attenuated by e ither haloperidol or ketanserin pretreatment thereby suggesting a role of both dopaminergic and tryptaminergic systems.

In summary, our data with the shock-induced depression model, suggest an antidepressant effect of the NMDA receptor antagonists namely, MK 80 I and ketamine, and a complexity of neurotransmitter mechanisms which are responsible for the occurrence of behavioural effects in thi s mode l. The present study demonstrated that brain noradrenergic, dopaminergic and tryptaminergic mechani sms ~re

involved in the behavioural suppression observed after inescapable foot shock. Furthermore, as the main action of antidepressants is (0 inhibit monoamine reuptake, they should be effective in countering the effect of inescapable shock45

, our study also demonstrates the effectiveness of both imipramine and the NMDA receptor antagonists in preventing the effects of inescapable foot shock. These findings combined with the observations of earlier workers suggest that the effect of shock upon animal behaviour is a useful model for studying the neurochemical basis of psychomotor retardation, which often occurs in endogenous depression.

Acknowledgement This study was supported by financial assistance

from CSIR, New Delhi.

References I Follesa P & Ticku MK, .1 NeU/'osci, 16 (1996) 140.

2 Foster AC, in Excitatory amino acid antagonists, editecf by Meldrum BS (Blackwell Scientific Publications, Oxford) 1991,164.

3 Patel S, Chapman AG, Milan MH & Meldrum BS , in Excitatory amino acids ill health and disease. edited by Lodge D (John Wiley & Sons, Chi chester) 1988, 353 .

4 Tricklebank MD, Singh L, Oles RJ. Preston C & In versen SD, Ellr.l Pharmacal , 167 (1989) 127.

5 Troupin AS , Mendius JR , Chang F & Ri singer MW. in Current problems ill epilepsy , edited hy Meldrum BS & Porter RJ (John Libbey. London ) 1986. 19 I .

6 Trimble M, Epilepsia , 19 (197)1) 241. 7 Trimble M, Neuropharmacologr. 19 (1980) 1227. 8 Aggarwal R, Dandiya PC & Vohora SR. Ill diwl .I

Pha"llacal, 24 ( 1992) 197. 9 BellS TA, in Epilepsv alld psrchial/T. edited hy Reynolds EH

& Trimble MR (Churchill Livingstone. New York ) 198 1.60. 10 Trullas R & Skolnick P, Ellr.l P//{/m/{/co /. 185 ( 1990) I .

II Wong EHF, Kemp JA . Priestl ey T. Knight AR, Woodruff GN, Iversen LL, Proc Na IL AC(I{/ Sci USA. 83 ( 1986) 7104.

12 Huellner JE & Bean BP, Proc N{I// Acw/ Sci USA . 85 ( 19X8) 1307.

13 Skolnick P, Marvizon JC, Jackson BW. Monn JA. Ri ce KC & Lewin AB, Life Sci. 45 (1989 ) 1647.

14 Danysz W, Plaznik A & Kostowski W. Phllm/(/co / Tllxico /, 62 (1988) 42 .

15 Plaznik A, Tamborska E. Hauptman M. 13idzin ski A & Kostowski W, Braill Res , 447 ( 1988 ) 122.

16 Shanks N & Anisman H, P.Hchophamlllco/lIgy. 99 ( 1989) 122.

17 Ani sman H & Zacharko RM , Be!wv Bmill Sci. 5 ( 1982) X9. 18 Maier SF, Prog NellroPsYc!lOphllnllllco/ /Jill/ Ps."chial. 8

( 1984) 435. 19 Pare WP & Glavin GB , Nelll'Osci Bio /u' /1lI 1' HI' v. 10 ( 1986)

339. 20 Edwards E, Johnson J. Anderson D. Turano P & Henn FA.

Pha rmacal Biachem Belial!. 25 ( 1986) 415 . 21 Pal SN & Dandiya Pc' Phamw(.'o/ Biochl'lIl Beha l'. 48

(1994) 845 . 22 Zacharko RM , Lalonde GT. Kasian M & Anisman H. Braill

Res, 426 (1987) 164. 23 Meloni D, Gambarana C, De Monti s MG. Dnl Pra P. Taddei

I & Tagliamonte A, Phanllacol l3iochell/ Be/WI '. 46 (1993) 423 .

24 Morelli M & Di Chiara G. EliI' .I Phw'IlIaco/. 182 (1990) 611.

25 Tiedtke PJ , Bischoff C & Schmidt WJ. j Neill'll/ TI'lIIlSIII , 81 (1990) 173.

26 Maj J, Rogoz Z & Skuza G. Po/ .I P/wmw('o / Phw'IlI , 43 (1991) 449.

27 Lynch DR & Gallagher, .I Phmww/ E.Il' Ther. 279 (1996) 154.

28 Anden NE, Carlsson A, Dahlstrom A. Flixe K. Hill arp A & Larsson K, Life Sci, "3 (1964) 523 .

29 Fallon JH & Moore RY , .1 Comp Nellro /. I RO ( l lJ7H) 545. 30 Cuenod M. Beaudet A. Canzek V. Streit P & Rellbi Jc, Adv

Biachem Psyclwpharmaca/, 27 ( IlJ81 ) 57 . 3 1 Maura G, Giardi A & Raiteri M . .I Phamwco/ Exp Th er. 247

(1988) 680. 32 Clow DW & Jhamandas K. J PharllJllco/ EXJI Ther. 248

(1989) 722. 33 Varma A & Kulkarni SK. P.I'vc/wphal'/lIl1c%gr. 107 (1992)

431. 34 Irifune M, Shimizu T & Nomoto M. Phanllllco/ Biochem

l3eha v, 40 (1991) 399. 35 Bannon MJ & Roth RH, Phal'lllllco/ Rev, 35 ( 1983) 53.

95x INDIAN J EXP BIOL, OCTOBER 1999

36 Anisman H & Zacharko RM, Pharmacol Ther, 48 (1990) 121.

37 Edwards E, Komrich W, Houuen PY & Henn FA, Neuropharmacology, 31 (1992) 323.

38 Weiss 1M, Stone EA & Harrel N, J Comp Physiol Psychol, 72 (1970) 153.

39 Hertting G, Axelrod J & Witby LG, J Pharmacol Exp Ther, 134 (1961) 146.

40 Ross SB & Renyi AL, Eur J Pharmacol, 4 (1969) 270.

41 Kulkarni SK & Dandiya Pc. P.I'vc/lOphal'/lwcologill , 27 (1972) 367.

42 Halaris AE, Belendluk KT & Freedman DX. Biochelll Pharmacol, 24 ( 1975) 1996.

43 Maj.l, Grabowska' M & Mogilnicka E. Psr c:holiharllla­cologia, 22 (l971 } 162.

44 Maj . .I , Rogoz Z & Skuza G. Pol .I PlllIrm(lco l PIW/'III , 44 (1992) 2 17.

45 Kametani H, Nomura S & Shimi zu J. P.I'rcltllpiwrlll(lcologr. 80 (1983).